DESCRIPTION (Applicant's Description): Mitochondria are remarkably dynamic organelles; they undergo cycles of fusion and fission, in some cases in response to developmental signals. The mitochondrial fusion process is unique among intracellular membrane fusion events, because each organelle contains two sets of lipid bilayers. Recent studies in yeast and flies have identified Fzo, a transmembrane GTPase localized to niitochondria, as an essential molecule in mitochondrial fusion. Moreover, these studies indicate that mitochondrial fusion is essential for normal respiratory function. Intriguingly, Fzo contains several coiled-coil motifs, reminiscent of viral envelope proteins and SNARE complexes that are directly involved in other types of membrane fusion. Little is known about the physiological role of mitochondrial fusion in mammalian development. In addition, the mechanism through which Fzo promotes mitochondrial fusion is unknown. This proposal addresses these issues with the following research goals: (1) to determine the role of mitochondrial fusion in mammalian development through developmental and cellular analysis of mice lacking homologs of Fzo, (2) to gain a detailed understanding of the structural domains of Fzo and the roles these domains play in mediating membrane fusion, (3) to identify other components of the fusion machinery through development of an in vitro mitochondrial fusion assay and isolation of Fzo-associated proteins. In addition to clarifying a basic cellular process, these studies may further understanding of human mitochondrial diseases and aging.